Synthesis of Glycyrrhetinic Acid-Modified Chitosan 5-Fluorouracil Nanoparticles and Its Inhibition of Liver Cancer Characteristics in Vitro and in Vivo

Abstract

Nanoparticle drug delivery (NDDS) is a novel system in which the drugs are delivered to the site of action by small particles in the nanometer range. Natural or synthetic polymers are used as vectors in NDDS, as they provide targeted, sustained release and biodegradability. Here, we used the chitosan and hepatoma cell-specific binding molecule, glycyrrhetinic acid (GA), to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by Fourier transformed infrared spectroscopy (FT-IR) and 1H-nuclear magnetic resonance (1H-NMR). By combining GA-CTS and 5-FU (5-fluorouracil), we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 217.2 nm, a drug loading of 1.56% and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained release system comprising three distinct phases of quick, steady and slow release. We demonstrated that the nanoparticle accumulated in the liver. In vitro data indicated that it had a dose- and time-dependent anti-cancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. Additionally, GA-CTS/5-FU significantly inhibited the growth of drug-resistant hepatoma, which may compensate for the drug-resistance of 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited tumor growth, resulting in increased survival time.

Assessment of sequential combination of 5-fluorouracil-loaded-chitosan-nanoparticles and ALA-photodynamic therapy on HeLa cell line

“…In the present study, 5Fu-CNPs were synthesized with the aim of prolonging drug action and thus improving therapeutic results. 5-Fu loaded into NPs based in chitosan could improve the bioavailability, the site-specific of delivery and reduction of its side-effects providing obvious therapeutic advantages [9,18]. incorporation into DNA leading to their break [24,25].…”

“…In this manner, small-molecule drugs, as 5-Fu, carried by chitosan or its derivatives, result in extended release, improved bioavailability and reduced side effects [9]. Due to its pivotal role in the treatment of a variety of solid tumors, 5-Fu remains as one of the most commonly used anticancer drugs and it has been included into a wide range of therapeutic programs, either alone or in combination with other drugs.…”

Carbohydrate-Based Materials for Targeted Delivery of Drugs and Genes to the Liver

“…GA-targeted nanoparticles showed high accumulation in hepatic cancer, 30 min postintravenous injection. Although, some tumor regression was observed upon treatment of mice with GA-CS-FU, the effect was not significantly different than FU alone [46]. Layer-by-layer assembly of chitosan bearing alkyne and azide functional groups on fluorescent calcium carbonate CaCO 3 colloids, yielded well defined microcapsules for in situ imaging.…”

Nanoformulations for Therapy of Pancreatic and Liver Cancers

“…Other chemotherapeutic agents delivered using CSNPs include 5-fluorouracil (5-FU) and camptothecin (CPT) [53][54][55]. 5-FU is a cytotoxic drug, which interferes with nucleic acid synthesis, inhibits DNA synthesis and eventually halts cell growth [56].…”